The need to treat elusive and debilitating disorders such as cancer, osteoporosis and other diseases involving untoward bone resorption (e.g., Paget's Disease, primary and secondary hyperparathyroidism, humoral hypercalcemia of malignancy, various cancers where resorption is increased, and rheumatoid arthritis), and disorders involving increased vascular permeability, to name a few, has led to extensive research on the mechanisms involved in disease initiation and/or progression and on the identification of new drugs which might interfere with those mechanisms.
One approach, for example, for treating bone disorders is inhibition of the osteoclast proton pump. See e.g., Blair et al., Science 1989, 245, 855-857; Finbow et al., Biochem. J. 1997, 324, 697-712; Forgac, M. Soc. Gen. Physiol. Ser. 1996, 51, 121-132; Baron et al., J. Cell. Biol. 1985, 101, 2210-2222; Farina et al., Exp. Opin. Ther. Patents 1999, 9, 157-168; and David, P. and Baron, R. “The Vacuolar H+-ATPase: A Potential Target for Drug Development in Bone Diseases” Exp. Opin. Invest. Drugs 1995, 4, 725-740.
Another approach to drug discovery for treating bone-related (and other) diseases involves the control of cellular signal transduction. See, for example, Missbach et al., “A Novel Inhibitor of the Tyrosine Kinase Src Suppresses Phosphorylation of Its Major Cellular Substrates and Reduces Bone Resorption In Vitro and in Rodent Models In Vivo.” Bone 1999, 24, 437-449; Connolly et al., Bioorg. & Med. Chem. Lett. 1997, 7, 2415-2420; Trump-Kallmeyer et al., J. Med. Chem. 1998, 41, 1752-1763; Klutchko et al., J. Med. Chem. 1998, 41, 3276-3292; Legraverend et al., Bioorg. & Med. Chem. 1999, 7, 1281-1293; Chang et al., Chem. & Biol. 1999, 6, 361-375; Lev et al. Nature 1995, 376, 737-784; Palmer et al., J. Med. Chem. 1997, 40,
Some approaches for the treatment of bone disorders such as osteoporosis include, for example, estrogens, bisphosphonates, calcitonin, flavonoids, and selective estrogen receptor modulators. Other approaches include peptides from the parathyroid hormone family, strontium ranelate, and growth hormone and insulin-like growth response (see, for example, Reginster et al. “Promising New Agents in Osteoporosis,” Drugs R & D 1999, 3, 195-201). Unfortunately, these therapeutic agents still have significant shortcomings.
The variety of different approaches represented by the therapeutic agents currently available or under study evidence the variety of biological factors influencing the competing processes of bone production and resorption. Although progress has been made towards developing therapeutic agents for osteoporosis and other bone disorders, there remains a need to develop new therapeutic agents which have an improved therapeutic index, which may be given to patients who cannot well tolerate or do not respond to existing therapies, and/or which may be used in conjunction with other therapies.
Protein kinases, specifically Src protein kinases, have been shown to play a crucial role in osteoclast function and thus in the resorption of bone and the progression of the osteoporosis. In addition, cellular signal transduction mediated by kinases like Src is believed to play a key role in other diseases, for example cancer and diseases involving increased vascular permeability. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation.
Several families of protein tyrosine kinases have been implicated in human cancer, including, but not limited to Src, Abl, Jak, Ack, Csk, Fak, Fes, Frk, Tec, and Syk, to name a few. For a detailed review of the role of oncogenic kinase signalling see, Blume-Jensen et al. Nature, 2001, 411, 355, and references cited therein.
Furthermore, certain kinases are believed to mediate signaling activity in response to a variety of growth factors, including VEGF, vascular endothelial growth factor, (see, Schlessinger, J. Cell 2000, 100, 293; Lowell et al. Genes Dev. 1996, 10, 1845), which is an angiogenic factor that promotes vascular permeability. The ability to control (and/or diminish) increased vascular permeability by suppression of a signalling pathway would be useful for the treatment of patients suffering from diseases and conditions related to increases in vascular permeability (e.g., edema, hemorrhage, cancer, vasular leaks, and the like). For a review of antiangiogenic agents (including those agents having antitumor activity), see Klohs et al., Curr. Opin. Biotechnol. 1999, 10, 544.
Although some progress has been made in the treatment of certain debilitating diseases and disorders mentioned herein, there remains a need to develop new therapeutic agents which have an improved therapeutic index, which may be given to patients who cannot well tolerate or do not respond to existing therapies, and/or which may be used in conjunction with other therapies. Thus, new, selective inhibitors of osteoclast activity and promoters of osteoblast activity as well as therapeutic agents that can regulate a variety of other signal transduction pathways would be desirable. Such compounds may then be used to inhibit or promote complex biological processes in order to treat and/or prevent diseases associated with signalling (e.g., osteoporosis, cancer and edema, to name a few).
1. General Description of Compounds of the Invention:
In recognition of the foregoing need, this invention provides a novel family of phenylamino-pyrimidines having useful biological and pharmacological properties.
These include compounds having the general formula I (and pharmaceutically acceptable derivatives thereof):                 or a pharmaceutically acceptable derivative thereof, wherein each occurrence of RA is independently hydrogen or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;        each occurrence of RB is independently aliphatic, heteroaliphatic, aryl or heteroaryl moiety; or is substituted or unsubstituted amino, alkoxy, amido, or carboxamido; or is         wherein each occurrence of RM is independently hydrogen or aliphatic;        X is O, S, NRM, or N(ORM);        V is O or —NH—;        n is 0 or 1;        r is 0, 1 or 2;        RE is an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;        each occurrence of RC and RD is independently H, halogen, —CN, —S(O)hRJ, —NO2, —CORJ, —CO2RJ, —NRJCORJ, —NRJCO2RJ, —CONRJRJ, −CO(NORJ)RJ, aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or -ZRJ;        wherein h is 1 or 2; and        Z is independently —O—, —S—, NRK, —C(O)—, wherein each occurrence of RJ and RK is independently hydrogen, CORL, COORL, CONRLRM, —NRLRM, —S(O)2RL, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, and wherein each occurrence of RL and RM is independently hydrogen, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;        each occurrence of y and z is independently 0, 1, 2 or 3, and the sum of y+z is an integer from 1-3, inclusive; and        each occurrence of w and x is independently 0, 1, 2, 3, 4 or 5, and the sum of w+x is an integer from 1-5, inclusive;        wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be linear or branched, cyclic or acyclic, saturated or unsaturated, and substituted or unsubstituted, and each aryl and heteroaryl moiety may be substituted or unsubstituted; and        at least one of RA, RB, RC or RD as defined above, contains a phosphorus-containing moiety.        
It will be appreciated that the compounds of the present invention are intended to encompass structures having a variety of phosphorus-containing moieties; however, in certain embodiments, one or more of RA-RD (and including RE-RH, as defined within RA-RD) as defined above or herein, contain one or more phosphorus moieties each independently a group having a structure from Series I below:                 wherein each occurrence of K is independently O or S;        each occurrence of Y is independently —O—, —S—, —NH—, —NR1, or a chemical bond linking R1 to P;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of R2 is independently R1, —PK(YR1)(YR1), —SO2(YR1) or —C(O)(YR1);        each occurrence of G is independently absent, or is —O—, —S—, —NR1— or (M)s;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6; and        each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted;        wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.        
In certain embodiments, M is —CRxRy, wherein each occurrence of Rx and Ry is independently hydrogen, halogen, alkyl, heteroalkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety. In certain exemplary embodiments, R1 is hydrogen or lower alkyl and M is —CH2—, —CH(OH)—, —CH(NH2)—, —C(alkyl)(OH)—, —C(alkyl)(NH2)—, —CH(halo)- or —C(halo)2-.
Exemplary phosphorus-containing moieties are further illustrated by the groups of Series Ia and Ib below:                 wherein each occurrence of Y is independently O or S;        each occurrence of Y is independently —O—, —S—, —NH—, —NR1—, or a chemical bond linking R1 to P;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of R2 is independently R1, —PK(YR1)(YR1), —SO2(YR1) or —C(O)(YR1);        each occurrence of G is independently absent, or is —O—, —S—, —NR1— or (M)s;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6; and        each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted; and        each occurrence of R4 is independently an aliphatic, heteroaliphatic, aryl or heteroaryl moiety;        wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.        
Exemplary phosphorus-containing moieties are further illustrated by Series Ic depicted below:                 wherein each occurrence of R1 is independently hydrogen, alkyl or aryl;        each occurrence of R4 is independently alkyl or aryl;        each occurrence of R6 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; and        each occurrence of R8 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, or a prodrug moiety;        wherein in each of the foregoing groups each alkyl or heteroalkyl moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.        
Exemplary phosphorus-containing moieties are further illustrated by Series II depicted below:                 wherein each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1—; —CO(Y′R1); —NR1(Y′R1); S(O)2(Y′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(O)2; and each occurrence of G is independently absent, or is —O—, —S—, —NR1—, S(O)2 or (M)s;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6;        PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib; or Series Ic, and m is an integer from 0-3, t is an integer from 1-3, and the sum of m+t is an integer from 1-5;        wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.        
Exemplary phosphorus-containing moieties are further illustrated by Series IIa below:                 wherein each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1; —CO(Y′R1); —NR1(Y′R1); S(O)2(Y′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(O)2;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of R2 is independently R1, —PK(YR1)(YR1), —SO2(YR1) or —C(O)(YR1); wherein each occurrence of Y is independently —O—, —S—, —NH—, —NR1—, or a chemical bond linking R1 to P;        each occurrence of G is independently absent, or is —O—, —S—, —NR1—, S(O)2, or (M)s;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6;        m is an integer from 0-3; and        PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib or Series Ic;        wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.        
Exemplary phosphorus-containing moieties are further illustrated by Series IIb:                 wherein K is O or S;        each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1; —CO(Y′R1); —NR1(Y′R1); S(O)2(Y′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(O)2;        each occurrence of Y is independently —O—, —S—, —NH—, —NR1—, or a chemical bond linking R1 to P;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of R2 is independently R1, —PK(YR1)(YR1), —SO2(YR1) or —C(O)(YR1);        each occurrence of G is independently absent, or is —O—, —S—, —NR1—, S(O)2, or (M)s;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6; and        each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted;        wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.        
Exemplary phosphorus-containing moieties are further illustrated by Series IIc below:                 wherein each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1; —CO(Y′R1); —NR1(Y′R1); S(O)2(Y′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(O)2;        each occurrence of R2 is independently R1, —PK(YR1)(YR1), —SO2(YR1) or —C(O)(YR1);        each occurrence of Y is independently —O—, —S—, —NH—, —NR1—, or a chemical bond linking R1 to P;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of G is independently absent, or is —O—, —S—, —NR1—, S(O)2, or (M)s;        each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6; and        m is an integer from 0-3;        wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.        
Exemplary phosphorus-containing moieties are further illustrated by Series III:                 wherein K is O or S;        each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1; —CO(Y′R1); —NR1(Y′R1); S(O)2(Y′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(O)2; and each occurrence of G is independently absent, or is —O—, —S—, —NR1—, S(O)2, or (M)s; wherein each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated; and each occurrence of s is independently an integer from 0-6        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.        
Exemplary phosphorus-containing moieties are further illustrated by Series IV below:                 wherein each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1; —CO(Y′R1); —NR1(Y′R1); S(O)2(Y′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(O)2; each occurrence of G is independently absent, or is —O—, —S—, —NR1—, S(O)2, or (M)s; and m is an integer from 0-4;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6;        each occurrence of R6 is independently hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety; and        each occurrence of R8 is independently hydrogen, an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or a prodrug moiety;        wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.        
Certain exemplary embodiments are described in more detail below and in the examples; however, it will be appreciated that the compounds of the invention are not limited by these examples.
2. Certain Featured Classes of Compounds of the Invention:
As discussed above, any one or more of RA-RD (and including RE-RH, as defined within RA-RD), as defined above or herein, contain one or more phosphorus-containing moieties.
It will be appreciated that in certain embodiments, any one or more of RA-RD, contain one or more of the following phosphorus-containing moieties of Series I depicted below:                 wherein each occurrence of K is independently O or S;        each occurrence of Y is independently —O—, —S—, —NH—, —NR1—, or a chemical bond linking R1 to P;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of R2 is independently R1, —PK(YR1)(YR1), —SO2(YR1) or —C(O)(YR1);        each occurrence of G is independently absent, or is —O—, —S—, —NR1— or (M)s;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6; and        each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted.        
In certain other embodiments, compounds as described generically above and as described in certain subsets herein, any one or more of of RA-RD contain one or more of the following phosphorus-containing moieties of Series Ia or Ib depicted below:                 wherein each occurrence of K is independently O or S;        each occurrence of Y is independently —O—, —S—, —NH—, —NR1—, or a chemical bond linking R1 to P;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of R2 is independently R1, —PK(YR1)(YR1), —SO2(YR1) or —C(O)(YR1);        each occurrence of G is independently absent, or is —O—, —S—, —NR1— or (M)S;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6; and        each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted; and        each occurrence of R4 is independently an aliphatic, heteroaliphatic, aryl or heteroaryl moiety. In certain embodiments, M is —CRxRy, wherein each occurrence of Rx and Ry is independently hydrogen, halogen, alkyl heteroalkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl heteroalkyl, aryl or heteroaryl moiety. In certain exemplary embodiments, M is —CH2—, —CH(OH)—, —CH(NH2)—, —C(alkyl)(OH)—, —C(alkyl)(NH2)—, —CH(halo)- or —C(halo)2-.        
In still other embodiments, any one or more of of RA-RD, as described directly above, contain at least one of the phosphorus-containing moieties in Series Ic depicted below:                 wherein each occurrence of R1 is independently hydrogen, alkyl or aryl;        each occurrence of R4 is independently alkyl or aryl;        each occurrence of R6 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; and        each occurrence of R8 is independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, or a prodrug moiety.        
In certain embodiments, R6 is hydrogen, lower alkyl, ORL or NRLRM; wherein each occurrence of RL and RM is independently hydrogen, or an alkyl, heteroalkyl, aryl or heteroaryl moiety. In certain other embodiments, R6 is hydrogen, methyl, ethyl, OH or NH2. In certain embodiments, R8 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl or a prodrug moiety. In still other embodiments, R8 is hydrogen, methyl, ethyl, or a prodrug moiety.
It will be appreciated that, in certain embodiments, any one or more of of RA-RD contain any one of the phosphorus-containing aryl of heteroaryl moieties of Series II:                 wherein each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1; —CO(Y′R1); —NR1(Y′R1); S(O)2(Y′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(O)2; and each occurrence of G is independently absent, or is —O—, —S—, —NR1—, S(O)2, or (M)s;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6;        PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib; or Series Ic, and m is an integer from 0-3, t is an integer from 1-3, and the sum of m+t is an integer from 1-5.        
In still other embodiments, any one or more of of RA-RD, as described directly above, contain a phosphorus-containing moiety of Series IIa depicted below:                 wherein each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1; —CO(Y′R1); —NR1(Y′R1); S(O)(Y′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(O)2;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of R2 is independently R1, —PK(YR1)(YR1), —SO2(YR1) or —C(O)(YR1); wherein each occurrence of Y is independently —O—, —S—, —NH—, —NR1—, or a chemical bond linking R1 to P;        each occurrence of G is independently absent, or is O—, —S—, —NR1—, S(O)2, or (M)s;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6;        m is an integer from 0-3; and        PCM is a phosphorus-containing moiety of Series I, Series Ia, Series Ib or Series Ic.        
In still other embodiments, any one or more of of RA-RD, as described directly above, contain a phosphorus-containing moiety of Series IIb depicted below:                 wherein K is O or S;        each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1; —CO(Y′R1); —NR1(Y′R1); S(O)2(Y′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(O)2;        each occurrence of Y is independently —O—, —S—, —NH—, —NR1—, or a chemical bond linking R1 to P;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of R2 is independently R1, —PK(YR1)(YR1), —SO2(YR1) or —C(O)(YR1);        each occurrence of G is independently absent, or is —O—, —S—, —NR1—, S(O)2, or (M)s;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6; and        each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted.        
In still other embodiments, any one or more of of RA-RD, as described directly above, contain a phosphorus-containing moiety of Series IIc depicted below:                 wherein each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1; —CO(Y′R1); —NR1(Y′R1); S(O)2(Y′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(O)2;        each occurrence of R2 is independently R1, —PK(YR1)(YR1), —SO2(YR1) or —C(O)(YR1);        each occurrence of Y is independently —O—, —S—, —NH—, —NR1—, or a chemical bond linking R1 to P;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of G is independently absent, or is —O—, —S—, —NR1—, S(O)2, or (M)s;        each occurrence of MY is independently a methine group or a lower alkyl moiety which contains a methine group and optionally may be further substituted;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6; and        m is an integer from 0-3.        
In still other embodiments, any one or more of of RA-RD, as described directly above, contain a phosphorus-containing moiety of Series III depicted below:                 wherein K is O or S;        each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1; —CO(Y′R1); —NR1(Y′R1); S(O)2(Y′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(O)2; and each occurrence of G is independently absent, or is —O—, —S—, —NR1—, S(O)2, or (M)s; wherein each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated; and each occurrence of s is independently an integer from 0-6        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H.        
In still other embodiments, any one or more of of RA-RD, as described directly above, contain a phosphorus-containing moiety of Series IV depicted below:                 wherein each occurrence of R3 is independently hydrogen; halogen; —CN; NO2; N3; R1; -GR1; —CO(Y′R1); —NR1(Y′R1); S(O)2(YR′R1); wherein each occurrence of Y′ is independently —O—, —S—, —NR1—, —C(O)—, —COO— or S(Ok; each occurrence of G is independently absent, or is —O—, —S—, —NR1—, —C(O)2, or (M)5; and m is an integer from 0-4;        each occurrence of R1 is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or, except in YR1 moieties in which Y is a covalent bond, R1 may also be H;        each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be electronically saturated or unsaturated;        each occurrence of s is independently an integer from 0-6;        each occurrence of R6 is independently hydrogen, aliphatic, heteroaliphatic, aryl or heteroaryl moiety; and        each occurrence of RB is independently hydrogen, an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or a prodrug moiety;wherein in each of the foregoing groups each aliphatic or heteroaliphatic moiety may be branched or unbranched, cyclic or acyclic and substituted or unsubstituted, and may contain one or more electronically unsaturated bonds, and each aryl and heteroaryl moiety may be substituted or unsubstituted.        
In certain embodiments, for each of the compounds as described above and herein, Y is a chemical bond linking the phosphorus atom to R1. In certain other embodiments Y is an oxygen atom. In still other embodiments, Y is a chemical bond linking the phosphorus atom to R1 and R1 is a lower alkyl group having 1-6 carbon atoms. In yet other subsets of the compounds as generally described above, RA is hydrogen or an aliphatic or heteroaliphatic moiety and RD is hydrogen.
In certain embodiments, for each of the compounds as described above and herein, Y is a chemical bond linking the phosphorus atom to R1. In certain other embodiments Y is an oxygen atom. In still other embodiments, Y is a chemical bond linking the phosphorus atom to R1 and R1 is an alkyl group having 1-6 carbon atoms. In yet other subsets of the compounds as generally described above, RA is hydrogen or a lower alkyl moiety. In still other embodiments K is oxygen.
These classes and subclasses are further exemplified, as will be discussed in greater detail below in the featured classes of compounds of the invention, for example by those compounds in which R1 is H or lower alkyl; MY is CH2—, —CH(OH)—, —CH(halo)-, or C(halo)2-; R4 is lower alkyl and R is H.
The following structures illustrate several exemplary types of compounds of the classes and subclasses as described above and herein. Other types will be readily apparent to the reader. 
Certain exemplary embodiments are described in more detail below and in the examples; however, it will be appreciated that the compounds of the invention are not limited by these examples.
In addition to the classes of compounds described above, a subset of compounds of Formula I which are of special interest consists of compounds having the structure of Formula Ia (with the various substituents as defined, e.g. in Section 1, above): 